Effect of topical azithromycin on posterior blepharitis
窑Clinical Research窑
Comparison of therapeutic effects of topical azithromycin
solution and systemic doxycycline on posterior
blepharitis
1
Department of Ophthalmology, Faculty of Medicine,
Hamadan University of Medical sciences, Hamadan
6516836595, Iran
2
Endocrine Research Center, Research Institute for Endocrine
Sciences, Shahid Beheshti University of Medical Sciences,
Tehran 193954763, Iran
3
Department of Orthodontics, Faculty of Dentistry, Hamadan
University of Medical Sciences, Hamadan 6516836595, Iran
Correspondence to: Sanaz Soheilifar. Tavoos Alley, Andalib
Avenue, Hamadan 6516836595, Iran. sanaz_soheilifar@
yahoo.com
Received: 2015-03-14 Accepted: 2015-07-20
Abstract
· AIM: To compare the effect of azithromycin drop and
doxycycline capsule on treatment of posterior blepharitis.
· METHODS: Fifty patients (100 eyes) with moderate
posterior blepharitis, randomly divided into two
therapeutic groups; all the patients got warm eyelid
compress and massage three times a day for 3wk. In
addition the first group got azithromycin 1% drop, twice
daily for 1wk and then one drop daily for 2wk. The
second group got oral doxycycline 100 mg daily for 3wk.
At the end of the research, patients' signs and symptoms
were compared together. ANOVA, Chi-square and Mann-
Whitney tests were used for statistical analysis.
·RESULTS: Topical therapy with azithromycin and oral
therapy with doxycycline relieved signs and symptoms
after 3wk. There were no significant differences between
symptoms healing rate and foreign body sensation
healing in these two groups ( >0.05). However,
azithromycin drop was more effective in reduction of eye
redness and doxycycline was more effective in
meibomian glands plugging healing and reducing the
corneal staining.
·CONCLUSION: Topical azithromycin could have similar
effects as oral doxycycline on posterior blepharitis in
improving subjective symptoms. However, doxycycline
can reduce objective signs such as ocular surface
staining and meibomian gland plugging more than
azithromycin.
·KEYWORDS: blepharitis; azithromycin; doxycycline
1016
DOI:10.18240/ijo.2016.07.14
Zandian M, Rahimian N, Soheilifar S. Comparison of therapeutic
effects of topical azithromycin solution and systemic doxycycline on
posterior blepharitis. 2016;9(7):1016-1019
INTRODUCTION
B
lepharitis or eyelid margin inflammation is one of the
most common ocular diseases encountered by eye care
professionals and is often characterized by erythematous,
thickened eyelid margins with dysfunctional meibomian
glands and accumulation of debris along the eyelid margin[1-4].
Common signs of chronic blepharitis are conjunctival
hyperemia, mucous secretion, meibomian gland dysfunction,
and superficial punctuate keratitis [3]. Patients with blepharitis
usually complain of itching, foreign body sensation, burning,
dryness, and tearing[3]. American Academy of Ophthalmology
classified the disease as anterior or posterior blepharitis,
according to whether it primarily affects the lash-bearing
region of the eyelids or meibomian gland orifices,
respectively [5]. However, it is clear that these classifications
are not mutually exclusive and are often observed together
because of the proximity of the areas involved[5].
Management of blepharitis may include daily eyelid
cleansing methods and the use of therapeutic agents that
reduce infection and inflammation [6-7]. There are no
established guidelines regarding therapeutic regimens but
antibiotics and topical corticosteroids can produce significant
improvement in signs and symptoms of blepharitis. In most
cases subjective symptoms may persist even when signs have
been improved[7].
Systemic therapy with low-dose doxycycline, a long-acting
semi-synthetic tetracycline, has become the treatment of
choice for patients whose symptoms and signs are not
adequately controlled [3]. It has been used to treat ocular
rosacea, improving irritation symptoms and increasing tear
film stability [8-9] . It has also been used to treat corneal
erosions [10-11]. Other than their antibacterial activity,
tetracyclines have anti-inflammatory and antiangiogenic
properties.
In fact, these compounds decrease the activity of
phospholipase A2 and reduce the production of interleukin
IL-1琢 and tumor necrosis factor (TNF)-琢 in corneal
 陨灶贼 允 韵责澡贼澡葬造皂燥造熏 灾燥造援 9熏 晕燥援 7熏 Jul.18, 圆园16
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epithelium [12-14]. At high concentrations, tetracyclines inhibit
staphylococcal exotoxin-induced cytokines and chemokines[15].
Gastro-intestinal effects including nausea, vomiting and
diarrhea are the side effects of tetracyclines and are common
especially with high doses and most of them could be
attributed to iritation of the mucosa [16]. Doxycycline is one of
the most common causes of drug induced esophageal ulcers[17].
Oral azithromycin therapy improves the signs and symptoms
associated with dry eyes [1,18]. It is believed that systemic
azithromycin penetrates into the ocular surface and remains
at therapeutic levels days after the cessation of the
medication [19]. Azithromycin is anti-inflammatory, inhibiting
proinflammatory cytokines, and is potent against Gram-
negative microorganisms [20]. Clinical trials have identified
topical azithromycin as a potentially effective treatment for
lid margin disease and meibomian gland dysfunction[21-23].
The aim of the present study was to compare the therapeutic
effects of topical azithromycin and oral doxycycline on
improving the signs and symptoms of posterior blepharitis.
SUBJECTS AND METHODS
Fifty patients (26 men, 24 women) with chronic blepharitis,
25-40 years old with the mean age of 33.88 依9.03y were
included in this study and randomly divided into two groups.
These two groups were matched by sex and age. All of the
patients instructed to use warm eyelid compress and massage
three times 1d for 3wk. In addition the first group received
azithromycin 1% drop (Azithromax, Sinadarou, Tehran,
Iran), twice daily for 1wk and then one drop daily for 2wk.
The second group received oral doxycycline 100 mg
(Doxycycline, Mahbandarou, Tehran, Iran) once daily for
3wk. All the experiments were approved by the Ethics
Committee in the Research Center of Hamadan University of
Medical Sciences and a written informed consent was
obtained from every participant in the study.
The patients were visited three times (at the beginning of the
study, 2 and 3wk after initiation of the treatment). On each
visit, conjunctival peripheral injection and corneal staining
were examined with slit lamp. Each of these features was
graded based on area involved from 1+ to 4+. For corneal
staining, cornea divided into four imaginary concentric cycles
and staining of most peripheral band recorded as 1+ and
central cycle as 4+. Furthermore bulbar conjunctiva
imaginary divided into four equal quadrants and grading was
done based on the number of involved quadrants. Subjective
symptoms including itching, irritation and lacrimation were
recorded in a check list as 0 for no symptom and 2+ for
severe symptoms. In addition Schirmer I test (2min test
without anesthesia) performed in all of the patients, while
considering more than 10 mm tear production as normal [24].
The presence of foreign body sensation and meibomian
glands plugging were also determined for all of the patients
in every visit.
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Table 1 Schirmer test mean in azithromycin group, results of
ANOVA
Visits Mean SD P
1st 6.12 5.89
2nd 7.12 6.51 0.287
rd
3 8.16 6.84
Table 2 Schirmer test mean in doxycycline group, results of
ANOVA
Visits Mean SD P
1st 9 5.64
2nd 9.9 6.07 0.246
3 rd
11.04 6.48
Statistical Analysis Analysis was performed using the
statistical package SPSS 16. ANOVA was used for
comparing the results of Schirmer test and Chi-square test
was used to compare signs and symptoms at different time
intervals within each group. Mann-Whitney test was used for
comparing sign and symptoms between the groups. The level
of significance for all tests was set at <0.05.
RESULTS
All patients in the azithromycin group completed the study
and none of them experienced side effects; however 6 out of
25 patients in doxycycline group (24%) left the study. In the
doxycycline group 6 out of 19 patients (31.5% ) reported
nausea and 2 patients (10.5%) complained of vomiting and
diarrhea. The results of this study showed that the reduction
of the signs and symptoms in the two groups was not affected
by sex ( >0.05).
The results of ANOVA test showed that Schirmer I test score
did not change significantly at different intervals in the two
groups (Tables 1, 2)
The scores of subjective symptoms including itching,
irritation, lacrimation and the frequency of foreign body
sensation decreased significantly during the treatment time
( <0.05, Tables 3, 4). However no significant difference was
found in the reduction of subjective symptoms score and
frequency of foreign body sensation from the 1st to the 3rd visit
between the groups ( >0.05, Tables 3, 4).
The mean score of peripheral injection was improved
significantly from the 1st to the 3rd visit in the two groups.
Furthermore the reduction of the peripheral injection score in
the azithromycin group was significantly more than the
doxycycline group ( <0.05, Table 5).
The mean score of corneal staining was improved
significantly from the 1st to the 3rd visit in the two groups.
Furthermore the reduction of corneal staining score in the
doxycycline group was significantly more than the
azithromycin group ( <0.05, Table 6).
The frequency of meibomian glands plugging reduced
significantly from the 1st to the 3rd visit in the two groups.
Furthermore the reduction of the meibomian glands plugging
1017
Effect of topical azithromycin on posterior blepharitis

Table 3 Subjective symptoms scores in the groups at different visits

Groups 1st visit 2nd visit 3rd visit P (Chi-square) 1st to 3rd visit difference P (Mann-Whitney)
Azitromycin 1.2 0.64 0.24 <0.01 0.96
0.701
Doxycycline 0.96 0.58 0.32 <0.01 0.64

Table 4 Frequency of foreign body sensation in the groups at different visits

Groups 1st visit 2nd visit 3rd visit P (Chi-square) 1st to 3rd visit difference P (Mann-Whitney)
Azithromycin 58% 44% 26% 0.016 28%
0.881
Doxycycline 54% 46% 28% 0.027 26%

Table 5 Peripheral injection scores in the two groups

Groups 1st visit 2nd visit 3rd visit P (Chi-square) 1st to 3rd visit difference P (Mann-Whitney)
Azithromycin 1.76 1.16 0.36 <0.01 1.4
0.041
Doxycycline 1.54 1.24 0.26 0.001 1.28

Table 6 Corneal staining scores in the two groups

Groups 1st visit 2nd visit 3rd visit P (Chi-square) 1st to 3rd visit difference P (Mann-Whitney)
Azitromycin 1.24 1.09 0.9 0.004 0.34
0.022
Doxycycline 1.66 1.26 0.36 <0.01 1.3

Table 7 Meibomian glands plugging frequency in the two group

Groups 1st visit 2nd visit 3rd visit P (Chi-square) 1st to 3rd visit difference P (Mann-Whitney)
Azitromycin 96% 68% 32% <0.01 64%
0.039
Doxycycline 96% 70% 14% <0.01 82%

frequency in the doxycycline group was significantly more
than the azithromycin group ( <0.05, Table 7).
DISCUSSION
In the present clinical trial it was found that topical therapy
with azithromycin and systemic treatment with doxycycline
relieved signs and symptoms of posterior blepharitis except
for Schirmer I test score. On the other hand, no significant
differences was demonstrated in improvment and healing of
the subjective symptoms, including foreign body sensation,
itching, irritation and lacrimation between patients treated
with azithromycin ophthalmic solution and patients treated
with doxycycline capsule. However azithromycin ophthalmic
solution led to more improvement in peripheral injection than
doxycycline capsule and doxycycline caused more
improvement in meibomian glands plugging and corneal
staining than azithromycin.
Igami [25]
in their clinical trial evaluated the effects of
oral azithromycin on posterior blepharitis. They graded the
subjective clinical outcomes and also performed tear
break-up time, Schirmer I test, corneal fluorescein staining
score and rose bengal staining score in all of the patients.
They observed that all clinical outcome scores showed
statistically significant improvement after treatment with oral
azithromycin, except for eyelid swelling. On the other hand
they found no statistically significant improvement on
average values of Schirmer I test, corneal fluorescein staining
score, and rose bengal staining score [25]. In the present study,
azithromycin ophthalmic solution improved subjective
1018
symptoms and no significant improvement was found in
Schirmer I test, similar to Igami 's[25] study.
In our study topical azithromycin instead of systemic
azithromycin was used in order to prevent potential systemic
side effects associated with oral administration. In addition
consuming oral azithromycin could result in microbial
resistance to this antibiotic, especially for staphylococous
species[26].
Iovieno [27]
in their study on patients with chronic
blepharitis concluded that 4wk treatment with doxycycline
significantly improved symptoms and signs, similar to our
study. Furthermore they found that this drug decreases matrix
metalloproteinase-9 activity and increase anti-lipase level in
tear film[27].
Foulks [15]
compared biochemical features of meibomian
gland secretions and subjective symptoms of patients with
meibomian gland dysfunction who were treated with topical
azithromycin and oral doxycycline. They resulted that oral
doxycycline treatment was slightly less effective in
improving foreign body sensation and the signs of plugging
and secretion and found more biochemical lipid quality
improvement with azithromycin treatment[15]. However, in the
present study, oral doxycycline had slightly better effect on
meibomian glands plugging than topical azithromycin and no
significant difference was found in foreign body sensation in
the two groups. This may be justified with larger number of
our cases and different treatment schedule and duration of
treatment compared to Foulks 's[15] study.

Long half life and low frequency of usage are advantages of
using azithromycin [26], but azithromycin solution is not
available as a generic drug in our country, while doxycycline
is readily available and it may be considered a disadvantage
of using azithromycine solution.
From economic point of view, the cost of using topical
azithromycin 1% (www.drugs.com/price-guide/azasite) for
14d (Azasite, Inspire Pharmaceuticals, Whitehouse station,
USA) is approximately four times more than using
doxycycline capsule 100 mg (Doxycycline Monohydrate,
Lupin Pharmaceuticals, Baltimore, Maryland, USA) for 28d
of treatment in US market[28].
Topical azithromycin could have similar effects as oral
doxycycline on posterior blepharitis in improving subjective
symptoms, however doxycycline can reduce objective signs
such as ocular surface staining and meibomian gland
plugging more than azithromycin. Regarding the
gastrointestinal complaints of the patients treated with
systemic doxycycline, azithromycin solution can be a
comparable choice with less systemic side effects in
treatment of posterior blepharitis.
ACKNOWLEDGEMENTS
Conflicts of Interest: Zandian M, None; Rahimian N,
None; Soheilifar S, None.
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